[nom]

SOK583 (INN: aflibercept) / NCT04864834

CSOK583A12301

A 52-week multicenter, randomized, double-masked, 2-arm parallel study to compare efficacy, safety and immunogenicity of SOK583A1 to Eylea , administered intravitreally, in patients with neovascular age-related macular degeneration

Statistical Analysis Plan (SAP)

Document type: · SAP Documentation

Document status: · Final V6.0

Release date: · 22-Jun-2023

Number of pages: · 38

Property of Hexal AG and [nom] Inc.

Confidential

May not be used, divulged, published or otherwise disclosed without the consent of Hexal AG and [nom] Inc.

Template Version 4.0, Effective from 23-Apr-2021

[nom].

S A P Fi n al V 6 . 0

C o nfi d e nti al · P a g e 2 of 3 8

C S O K583 A1 2301

D o c u m e nt Hi st or y – C h a n g e s c o m p ar e d t o pr e vi o u s fi n al v er si o n of S A P

D at e · Ti m e · R e a s o n f or

p oi nt · u p d at e

1 3 -A pr - · Pri or · Cr e ati o n of fi n al

2021 · to D B · v er si o n

lock

2 8 -F e b - Pri or · U p d at e s m a d e

2022 · to D B · t o b e c o n si st e nt

lock · wit h a m e n d e d

st u d y pr ot o c ol

0 8- N o v - Pri or · U p d at e s m a d e

2022 · to D B · t o b e c o n si st e nt

lock · wit h a m e n d e d

st u d y pr ot o c ol a n d m ail c o m m u ni c ati o n t o u p d at e st u d y tr e at m e nt n a m e.

O ut c o m e · S e cti o n a n d titl e i m p a ct e d ( C urr e nt)

f or u p d at e

N/ A - Fir st · NA

v er si o n

Sec on d · G e n er al u p d at e: n e w S A P t e m pl at e w a s

v er si o n · a p pli e d. W or di n g s w er e u p d at e d t o i n cr e a s e

cl arit y .

S e cti o n 1: st u d y d e si g n fi g ur e w a s u p d at e d a s p er t h e a m e n d e d st u d y pr ot o c ol ( V 3. 0). N e w

T a bl e 1 -1 Pri m ar y a s s e s s m e nt s c h e d ul e w a s a d d e d. Ori gi n al T a bl e 1 -1 w a s u p d at e d t o T a bl e

1- 2 O bj e cti v e s a n d r el at e d e n d p oi nt s

E sti m a n d s w a s m o v e d t o s e cti o n 1. 2 p er n e w

S A P t e m pl at e a n d t h e w or di n g s w er e u p d at e d a s p er t h e a m e n d e d st u d y pr ot o c ol ( V 3. 0).

T a bl e 2 -1: a d diti o n al crit eri a w e r e u p d at e d.

S e cti o n 2. 5: c o -pri m ar y e sti m a n d w a s r e m o v e d.

Mi s si n g d at a h a n dli n g m et h o d s w er e u p d at e d a s p er t h e a m e n d e d st u d y pr ot o c ol ( V 3. 0).

V er si o n 3. 0 · S e cti o n 1. 2 : C CI

a n d u p d at e t o ti m e p oi nt f or s e c o n d ar y e n d p oi nt b a s e d o n C N V l e si o n si z e.

S e cti o n 2. 2 : All E nr oll e d A n al y si s S et a n d V E G F A n al y si s S et a d d e d .

S e cti o n 2. 2. 1: B at c h wi s e s u b gr o u p a n al y si s r e m o v e d.

S e cti o n 2. 8 : U p d at e d o n P K E n d p oi nt t o a d d a n al y si s o n P K Si mil arit y

S e cti o n 2. 9 a d d e d f or a n al y si s of P h ar m a c o d y n a mi c E n d p oi nt.

S e cti o n 5. 3. 3 a d d e d t o a d dr e s s st ati sti c al a n al y si s o n e n d p oi nt b a s e d o n P K Si mil arit y.

St u d y Tr e at m e nt n a m e S O K 5 8 3 A 1 u p d at e d t o

S O K 5 8 3 b a s e d o n m ail c o m m u ni c ati o n.

S e cti o n 2. 2 , 2. 3. 2, 2. 7. 1 : All E nr oll e d A n al y si s

S et a d d e d a n d Li sti n g s t o pr o vi d e d b a s e d o n All

E nr oll e d S et f or D e m o gr a p hi c , A E & M e di c al

Hi st or y .

S e cti o n 2. 3. 1 : A n al y si s o n R e a s o n f or S cr e e n f ail ur e r e m o v e d.

S e cti o n 2. 3. 2: M e di c al Hi st or y A d d e d a n d a n al y si s s et c h a n g e d f or D e m o gr a p hi c li sti n g.S e cti o n 2. 6. 3 a d d e d o n a n al y si s of J a p a n e s e P o p ul ati o n.

S e cti o n 2. 7. 1: B at c h wi s e a n al y si s r e m o v e d f or A E t a bl e s.

Hexal AG and [nom] Inc.

SAP Final V6.0

Date · Time · Reason for

point · update

24-Mar- Prior · - PD criteria

2023 · to DB · updates,

Lock · analysis added

for study

procedure, CM

& TEAE

definition

updates,

• Sensitivity

Analysis

removed due to no missing values, Immunogenicity analysis updated to reflect overall evaluation for both W40 and W52.

• Information on prohibited medication / procedure added.

Confidential · Page 3 of 38

CSOK583A12301

Outcome · Section and title impacted (Current)

for update

Section 2.8, 2.9: Section Updated for analysis part.

Section 2.10.3 updated

Section 5.3.3 & 5.4 added.

Table 2-1, Criteria added

Version 4.0 · 1. MedDRA Version updated

• Table 2-1 updated by updating information in

COMD01, COMD02 and removal of PD

OTH22.

Section 2.3.1 updated for change in population set of Importatnt PD listings and population set of analysis set table.

• Section 2.2 updated to clarify the term

“requiring” in the definition of PKS and VEGF analysis set.

• Section 2.2.1 subgroup analysis added on

TEAE by sugroup of interest.

• Section 2.5.7 merged with section 2.2.1
• Section 2.2.1 updated on Japan population consideration.
• Section 2.4 updated for more brief definion of Concomitant Medication.
• Section 2.4.1 & 2.4.2 updated for precise information on analysis.
• Section 2.6.2 updated based on analysis on

BCVA to display for all post-baseline visits. -

CNV values with CNV ABSENT will be considered as Zero for analysis purpose.

• Section 2.7.1 updated to add analysis on

Ocular TEAE related on study procedure.

• Updates to perform sensitivity analysis based on fellow-eye.

-TEAE definition updated in more brief.

• Relationship of Study procedure and Injection procedure.
• Section 2.7.4.2 updated for additional information on value consideration for post- injection IOP based on communication with

Medical Lead.

• Section 2.7.1.1 updated to substitute AESI as “AE according to the risks listed in Eylea EU RMP” as decided in November’s [nom] Strategy Team 2.0.
• Subgroup analysis based on Japanese population is removed except for analysis output same as primary objective as per

[nom] Strategy Team decisions.

Hexal AG and [nom] Inc.

SAP Final V6.0

Date · Time · Reason for

point · update

03-Apr- · Before To align with

2023 · DBL · condition of

protocol on prohibited medication

22-Jun- · Before Update for final

2023 · Week · analysis; VEGF

52 · analysis set

(Final) definition

DBL · update,

updates in Persistent definition for Overall (Week

52)

Confidential · Page 4 of 38

CSOK583A12301

Outcome · Section and title impacted (Current)

for update

• Section 5.1.4 added for partial nAMD start date imputation. Section 5.1 updated for AE & CM imputation rule as per data cut-off.
• Section 5.4 ATC code list updated & List of

Prohibited procedures

• Section 2.10.2 updated to add analysis on duration of exposure.
• Sensitivity Analysis of Primary endpoint based on LOCF approach is removed from analysis.
• Section 2.7.4.3 updated to perform overall evaluation At Week 40 & Week 52 both. definition added on persistent.

Version 5.0 · 1. Updates in Table 2-1 to clearly specify

prohibited medication criteria and to align as per protocol defined.

• Section 2.2 , Handling analysis scenario if subject receives both treatments into the study eye.

Version 6.0 · Section 2.2 , 2.3.1, 2.7.1, 2.7.4.3, 5.3.4

Hexal AG and [nom] Inc. · Confidential · Page 5 of 38

SAP Final V6.0 · CSOK583A12301

Table of contents

Table of contents ................................................................................................................. 5

List of tables ........................................................................................................................ 6

List of figures ...................................................................................................................... 7

List of abbreviations ............................................................................................................ 8

1 · Introduction ....................................................................................................................... 10

1.1 · Study design........................................................................................................... 10

1.2 · Study objectives and endpoints and estimands ...................................................... 11

1.2.1 · Primary estimand(s) .............................................................................. 12

2 · Statistical methods ............................................................................................................. 13

2.1 · Data analysis general information ......................................................................... 13

2.1.1 · General definitions ................................................................................ 14

2.2 · Analysis sets .......................................................................................................... 14

2.2.1 · Subgroup of interest .............................................................................. 18

2.3 · Subject disposition, demographics and other baseline characteristics .................. 18

2.3.1 · Subject disposition ................................................................................ 18

2.3.2 · Demographics and other baseline characteristics ................................. 19

2.4 · Treatments (study treatment, concomitant therapies, compliance) ....................... 20

2.4.1 · Study treatment / compliance ................................................................ 20

2.4.2 · Prior, concomitant and post therapies ................................................... 20

2.5 · Analysis supporting primary objective(s) .............................................................. 20

2.5.1 · Primary endpoint(s) ............................................................................... 21

2.5.2 · Statistical hypothesis, model, and method of analysis .......................... 21

2.5.3 · Handling of intercurrent events ............................................................. 22

2.5.4 · Handling of missing values not related with intercurrent events .......... 22

2.5.5 · Sensitivity analyses ............................................................................... 22

2.5.6 · Supplementary analyses ........................................................................ 22

2.6 · Analysis supporting secondary efficacy objective(s) ............................................ 22

2.6.1 · Secondary endpoints ............................................................................. 22

2.6.2 · Statistical hypothesis, model, and method of analysis .......................... 23

2.7 · Safety analyses ....................................................................................................... 23

2.7.1 · Adverse events ...................................................................................... 24

2.7.2 · Deaths .................................................................................................... 25

2.7.3 · Laboratory data ..................................................................................... 25

2.7.4 · Other safety data ................................................................................... 26

2.8 · Pharmacokinetic endpoints .................................................................................... 27

[nom]. · C o nfi d e nti al · P a g e 6 of 3 8

S A P Fi n al V 6 . 0 · C S O K583 A1 2301

• 9 · P h ar m a c o d y n a mi c e n d p oi nts ................................................................................. 2 8
• 1 0 · Ot h er a d diti o n al a n al ys es ....................................................................................... 2 8
• 1 0. 1 · A d diti o n al a n al ys es f or p u bli c ati o n p ur p os es ....................................... 2 8
• 1 0. 2 · A n al ys es f or t h e Ris k M a n a g e m e nt Pl a n .............................................. 2 8
• 1 0. 3 · A n al ys es f or r es ults p osti n g t o E u dr a C T a n d [nom] Tri als. g o v .......... 2 9
• 1 1 I nt eri m a n al ysis ...................................................................................................... 2 9 3 · S a m pl e si z e c al c ul ati o n ..................................................................................................... 2 9
• 1 · Pri m ar y e n d p oi nt(s) ............................................................................................... 2 9
• 2 · S e c o n d ar y e n d p oi nt(s) ........................................................................................... 3 1 C CI 5 · A p p e n di x ........................................................................................................................... 3 2
• 1 · I m p ut ati o n r ul es ..................................................................................................... 3 2
• 1. 1 · St u d y tr e at m e nt ..................................................................................... 3 2
• 1. 2 · A E d at e i m p ut ati o n ............................................................................... 3 2
• 1. 3 · C o n c o mit a nt m e di c ati o n a n d n o n- dr u g t h er a p y/ pr o c e d ur e d at e i m p ut ati o n ............................................................................................. 3 3
• 1. 4 · P arti al st art d at e f or n A M D ................................................................... 3 4
• 2 · A Es c o di n g/ gr a di n g ............................................................................................... 3 4
• 3 · St atisti c al m o d els ................................................................................................... 3 5
• 3. 1 · Pri m ar y a n al ysis .................................................................................... 3 5
• 3. 2 · S e nsiti vit y a n al ysis ................................................................................ 3 5
• 3. 3 · P K A n al ysis ........................................................................................... 3 5
• 3. 4 · R ul e of e x cl usi o n crit eri a of a n al ysis s ets ............................................. 3 6
• 4 · Pr o hi bit e d M e di c ati o ns a n d Pr o c e d ur es ................................................................ 3 6
• 4. 1 · A T C c o d es f or a nti- V E G F tr e at m e nt .................................................... 3 6
• 4. 2 · A T C c o d es f or c orti c ost er oi d tr e at m e nt ................................................ 3 7
• 4. 3 · Pr ef err e d T er ms f or Pr o hi bit e d Pr o c e d ur es ........................................... 3 7 6 · R ef er e n c es ......................................................................................................................... 3 7

Li st of t a bl e s

T a bl e 1 - 1 · Pri m ar y ass ess m e nt s c h e d ul e ................................................................ 1 1

T a bl e 1 - 2 · O bj e cti v es a n d r el at e d e n d p oi nts .......................................................... 1 1

T a bl e 2 - 1 · I m p ort a nt pr ot o c ol d e vi ati o ns l e a di n g t o e x cl usi o n fr o m P P S .............. 1 5

T a bl e 2 - 2 · L a b or at or y ass ess m e nts ......................................................................... 2 5

T a bl e 3 - 1 · Tr e at m e nt L e ast S q u ar e M e a ns at W e e k 8 ............................................ 3 0

T a bl e 3 - 2 · Diff er e n c es of Tr e at m e nt L e ast S q u ar e M e a ns at W e e k 8 .................... 3 0

Hexal AG and [nom] Inc.

SAP Final V6.0

Table 3-3

Table 5-1

List of figures

Figure 1-1

Confidential · Page 7 of 38

CSOK583A12301

Assumptions for sample size calculations based on FDA and EMA requirements .......................................................................................... 31

Participant classification ....................................................................... 36

Study Design ......................................................................................... 11

Hexal AG and [nom] Inc.

SAP Final V6.0

Confidential · Page 8 of 38

CSOK583A12301

List of abbreviations

ADA

AE

AESI

ANCOVA

ATC

BCVA

CI

CM

CNV

COVID-19

CRC

CSR

CSFT

CTD

CV

eCRF

eCRS

ETDRS

EqM

Eylea EU

FA

FAS

FCS

FDA

GCV

GM

GMR

IAS

ICF

IOP

IRT

IVT

LS

LLOQ

MedDRA

MMRM

nAMD

PD

PK

PKS

PMDA

Anti-drug antibody

Adverse event

Adverse event of special interest

Analysis of covariance

Anatomical Therapeutic Chemical

Best-Corrected Visual Acuity

Confidence interval

Concomitant medication

Choroidal neovascularization

Coronavirus disease of 2019

Central Reading Center

[nom] study report

Central Subfield Thickness

Common Technical Document

Coefficient of variation

Electronic Case Report/Record Form

Electronic Case Retrieval Sheet

Early Treatment Diabetic Retinopathy Study

Equivalence margin

EU-authorized Eylea ; the registered trademark sign “ ” will be omitted for Eylea in this document

Fluorescein Angiography

Full Analysis Set

Fully conditional specification

Food and Drug Administration

Geometric coefficient of variation

Geometric mean

Geometric mean ratio

Immunogenicity analysis set

Informed Consent Form

Intraocular pressure

Interactive Response Technology

Intravitreal

Least Squares

Lower limit of quantification

Medical dictionary for regulatory activities

Mixed-model repeated measures

Neovascular age-related macular degeneration

Protocol deviation

Pharmacokinetic(s)

PK Analysis Set

Pharmaceuticals and Medical Devices Agency (Japan)

Hexal AG and [nom] Inc.

SAP Final V6.0

PP

PPS

PT

RAS

RMP

SAE

SAF

SAP

SAS

SD

SD-OCT

SE

SOC

SOK583

TEAE

TFL

VEGF

WHODD

Confidential · Page 9 of 38

CSOK583A12301

Per-protocol

Per-protocol analysis set

Preferred Term

Randomized analysis set

Risk Management Plan

Serious adverse event

Safety analysis set

Statistical Analysis Plan

Statistical Analysis System

Standard deviation

Spectral-Domain Optical Coherence Tomography

Standard error

System Organ Class

Product code of [nom]’ proposed aflibercept containing biosimilar product

Treatment-emergent adverse event

Tables, Figures and Listing

Vascular Endothelium Growth Factor

World Health Organization Drug Dictionary

Hexal AG and [nom] Inc. · Confidential · Page 10 of 38

SAP Final V6.0 · CSOK583A12301

1 · Introduction

The purpose of the SAP is to describe the implementation of the statistical analyses planned in the protocol. The analyses described are based on the [nom] Study Protocol (CSP) Version

4.0 (incorporating amendment 3), dated 28-Jun-2022, and on the Annotated Case Report Forms

(aCRF), dated 15-Feb-2023. The operational part of the study, including the statistical programming, will be conducted by a CRO.

The planned analyses and the results for this study will be presented in the CSR for primary and final analyses. The primary CSR will include the analyses from the interim analysis performed at Week 40, and the final CSR, the cumulative analyses at Week 52.

A detailed description of the planned TFLs to be presented in the CSRs will be provided in accompanying TFL Shells document. TFLs with new data after primary analysis will be generated for the final analysis at Week 52. TFLs for primary endpoint analysis and baseline data are not planned to be reproduced.

Any deviations from this SAP with rationale will be described in the CSR.

1.1 · Study design

Study CSOK583A12301 is an international, multicenter, randomized, double-masked, 2-arm parallel study, in patients with nAMD, with a total duration of 52 weeks. A total of 460 study participants will be randomized at Baseline in a 1:1 ratio into either the SOK583 or the Eylea

EU treatment group.

Randomization will be stratified by the following factors:

For participants of the PK substudy (those who sign both the main ICF and the PK ICF), randomization will be stratified by age category (< 75 years and ≥ 75 years) and Baseline BCVA category. A list of randomization numbers will be generated by IRT with a 1:1 randomization ratio to SOK583 or Eylea EU.

For all other participants (those who sign the main ICF only), randomization will be stratified by region, age category and Baseline BCVA category and a list of randomization numbers will be generated by IRT with a 1:1 randomization ratio to SOK583 or Eylea EU.

The study consists of 3 periods: a Screening Period of up to 2 weeks (+ 1 week in case of technical errors, e.g. laboratory results could not be obtained, samples were lost, destroyed, hemolized, or images were of insufficient quality) to assess participant’s eligibility, the Treatment Period (Baseline to Week 48) and a Follow-up Period (Week 48 to Week 52).

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SAP Final V6.0 · CSOK583A12301

Figure 1-1 · Study Design

Only 1 eye will be selected as study eye and treated with study treatment (SOK583 or Eylea

EU). During the Treatment Period, participants will receive a [information personnelle] IVT injection of fixed 2 mg of SOK583 or Eylea EU in the study eye, every 4 weeks (q4w) at Baseline, Week 4 and Week 8, and thereafter every 8 weeks (q8w) at Weeks 16, 24, 32, 40 and 48.

Table 1-1 · Primary assessment schedule

Period · Treatment · Follow

-up

Visit Name · Scree Base Treatment Period · Safety

ning · line · (EOS)

Week · 1 · 4 · 8 · 16 · 24 · 32 · 40 · 48 · 52

Visit number · V1 · V2 · V3 · V4 V5 · V6 · V7 · V8 · V9 · V10 · V11

BCVA 1 · X · X · X · X · X · X · X · X · X · X · X

SOK583/ Eylea · X · X · X · X · X · X · X · X

EU IVT

administration

X=assessment to be recorded in the [nom] database or received electronically from a vendor

1 Assessments must be done prior to the IVT injections; BCVA must be performed in the study eye in all visits and in both eyes at Screening; at Baseline, only study eye BCVA needs to be tested and documented at eCRF; in cases where both eyes are eligible per Screening data, BCVA has to be performed for both eyes at Baseline in order to select the Study eye.

1.2 · Study objectives and endpoints and estimands

Table 1-2 · Objectives and related endpoints

Objective(s) · Endpoint(s)

Primary Objective(s) · Endpoint(s) for primary objective(s)

• To demonstrate similar efficacy of SOK583 · • · Mean change from baseline in BCVA score and Eylea EU in terms of BCVA · using ETDRS testing charts at Week 8 Secondary Objective(s) · Endpoint(s) for secondary objective(s)
• To evaluate if the anatomical outcome of · • · Mean change in CSFT using SD-OCT from SOK583 is similar to Eylea EU · Baseline to Week 1, 4, 8, 24 and 52

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SAP Final V6.0 · CSOK583A12301

Objective(s) · Endpoint(s)

• Mean change of CNV lesion size using FA from Screening to Week 8 and 52
• To evaluate if the efficacy of SOK583 is · • · Mean change from Baseline in BCVA score similar to Eylea EU in terms of BCVA · using EDTRS testing charts at Week 24 and 52
• To evaluate if SOK583 is similar to Eylea · • · Incidence of ocular and non-ocular AEs over EU in terms of safety · 52 weeks
• To evaluate if SOK583 is similar to Eylea · • · [nom] of binding and neutralizing EU in terms of immunogenicity · ADAs up to Week 52
• To evaluate the systemic exposure of · • · Aflibercept concentration assessments at SOK583 and Eylea EU in patients of the · Baseline (pre-dose) and 24 hours after the PK assessment · first and third injections Exploratory Objective · Endpoint for exploratory objective To evaluate systemic VEGF concentrations in · • · VEGF concentration assessment at Week 48 participants treated with SOK583 or Eylea EU · (pre-dose) and Week 52 1.2.1 · Primary estimand(s) The primary [nom] question of interest is: Does SOK583 have similar efficacy as Eylea EU in terms of mean change in BCVA score in participants with nAMD who are anti-VEGF naive, without important protocol deviations and adherent to the treatment and completed the treatment to Week 8?

The justification for using observed per-protocol (PP) estimand (Lou et al 2019) as the primary estimand is that given the sequential approach of biosimilar [nom], similarity between test and reference product on an analytical and [nom] level will have already demonstrated before the initiation of the [nom] studies. This provides a rationale to assume that the ideal-exact equality condition is satisfied. The observed PP estimand will also prioritize sensitivity to detect differences between treatments if any exists by assessing the treatment effect for participants who follow the intention of the protocol as closely as possible.

The primary estimand is described by the following attributes:

• Population: anti-VEGF treatment-naïve patients with nAMD without important protocol deviations and adherent to the treatment and completed the treatment (2 IVT injections) to Week 8). Important protocol deviations which affect the primary endpoint are provided in Table 2-1.
• Endpoint: change from baseline in BCVA score at Week 8
• Treatment of interest: the randomized treatment (SOK583 or Eylea EU).
• Since the primary analysis is only on those participants who adhere to and complete treatment and do not have important protocol deviations, there will be no intercurrent events for the observed PP estimand.
• The summary measure: difference in mean change from baseline to Week 8 in BCVA scores between SOK583 and Eylea EU.

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SAP Final V6.0 · CSOK583A12301

2 · Statistical methods

Analysis of the primary endpoint (mean change from Baseline in BCVA at Week 8) will be conducted on all patients with nAMD who are anti-VEGF naive, without important protocol deviations and adherent to the treatment and completed the treatment (2 IVT injections) to Week 8 for the interim analysis. Any efficacy and safety data of study participants collected during the study will also be analyzed for the final analysis.

FDA, EMA and PMDA have different requirements for equivalence testing of the primary endpoint:

• EMA and PMDA equivalence testing requirements: To demonstrate the equivalence of the difference in change from baseline at Week 8 in BCVA, the resulting 95% CI of the difference must lie within the equivalence interval of [-3.5, +3.5].
• FDA equivalence testing requirements: To demonstrate the equivalence of the difference in change from baseline at Week 8 in BCVA, the resulting 90% CI of the difference must lie within the equivalence interval of [-3.0, +3.0].

2.1 · Data analysis general information

Data will be analyzed by the CRO Biostatistics and Statistical Programming group according to the data analysis Section 12 of the study protocol and analyses planned in this document unless otherwise specified.

All statistical analyses will be performed using SAS (SAS Institute, Cary NC, USA, version

9.4 or higher version).

Medical coding will be conducted for AEs and Medical History using MedDRA version 26.0 or higher. Coding for medication and procedures will be performed using WHODrugGlobalB3

Mar 2023 or later.

There will be 2 analysis time points in this study. The first and interim analysis will be performed when all randomized participants have completed Week 40 or discontinued before

Week 40. This analysis is considered as the primary analysis. The second and final analysis will be performed when all participants have completed the study.

The primary analysis at Week 40 will be performed with an unmasking of specified individuals from the Sponsor who are not involved in the direct conduct of the study. The biostatistician who is directly involved in the conduct of the study will remain masked to treatment assignments while the study is in progress.

A blinded/unblinded charter document will summarize the procedures and actions to maintain masking to the actual treatment assignment. This document will be finalized prior to unmasking of the study at the time of the primary analysis at Week 40.

The statistical analyses described in this document cover the analyses for both the primary analysis at Week 40 and the second and final analysis.

Unless otherwise indicated, continuous variables will be summarized with the following descriptive statistics: n (number of observations), mean, SD, minimum, median, and maximum.

Categorical data will be summarized with frequencies and percentages. Percentages by categories will be based on the number of patients included in the analysis set under

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SAP Final V6.0 · CSOK583A12301

consideration unless otherwise specified. Where appropriate, two-sided CIs for point estimates of the mean or proportion will be provided. Point estimates and two-sided CIs of treatment group differences will be provided as appropriate.

Summary statistics will be presented by treatment group (and day and time point, as applicable) unless otherwise stated.

The following treatment groups will be presented:

• SOK583
• Eylea EU
• Total (wherever required)

2.1.1 · General definitions

Investigational treatment or study treatment refers to SOK583 2mg and Eylea EU 2mg IVT injections.

Baseline (Day 1) is the date of the first study treatment in the study. Baseline assessment is defined as the last available assessment collected prior to the first study treatment. Baseline assessments may occur at Baseline or Screening visits.

All data collected after the first study treatment are defined as post-baseline.

The study day for a post-baseline scheduled or unscheduled visit is defined as:

Study day = (date of visit) – (date of first study treatment) + 1

The study day for a scheduled or unscheduled visit before Baseline is defined as:

Study day = (date of visit) – (date of first study treatment)

On-treatment assessment/event is defined as any assessment/event in the period after the first dose of study treatment and on or before last administration of study treatment plus 4 weeks (28 days).

End of Study (EOS) refers to the EOS visit if used in the context of individual participant.

All data collected at unscheduled visits will not be used in ‘by-visit’ tabulation or graphs, but will be included for analyses based on all post-baseline assessments, such as safety narratives, summary of maximum decrease or increase from Baseline for laboratory and vital signs data.

All data collected at unscheduled visits will be included in listings.

2.2 · Analysis sets

All Enrolled Analysis Set

All Enrolled Set consists of all participants who signed the Informed Consent Form.

Randomized Analysis Set

The Randomized Analysis Set (RAS) consists of all randomized study participants. The RAS will include all study participants who were randomized including those that were not treated.

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Participants will be analyzed according to the treatment they have been assigned to during the randomization procedure.

Full Analysis Set

The Full Analysis Set (FAS) comprises all randomized participants to whom study treatment has been assigned by randomization, to whom at least 1 dose of study treatment has been administered and for whom at least 1 post-baseline BCVA value is available. According to the intent to treat principle, participants will be analyzed according to the treatment they have been assigned to during the randomization procedure.

Safety Set

The Safety Set (SAF) includes all randomized participants who received at least 1 dose of study treatment. Participants will be analyzed according to the study treatment received. Participants received multiple treatments (i.e. both SOK583 and Eylea EU) into the study eye will be analyzed according to the treatment arm from which they received majority of treatments up to the last treatment received. In case of received equal number of treatments it will be analyzed according to the first treatment received.

Per-protocol Set

The Per-protocol Set (PPS) is a subset of the FAS and is characterized by the following criteria:

• The primary BCVA assessments at baseline and Week 8 are available
• The participants received treatment according to the protocol at Day 1 and Week 4
• The participants have not experienced any important protocol deviations affecting the primary endpoint up to Week 8 The criteria to qualify a protocol deviation as important regarding the evaluation of the study’s primary objective is provided in Table 2-1.

Table 2-1 · Important protocol deviations leading to exclusion from PPS

PD identifier · Protocol deviation term for reporting · Additional criteria

INCL03 · Participant is not anti-VEGF naive for both eyes

and systemically

INCL04 · Study eye: absence of CRC confirmed active

nAMD in appropriate location

INCL06 · Study eye: BCVA not between 73 and 38 letters,

inclusive, at Baseline

EXCL01 · Both eyes: participant received previous treatment

with anti-VEGF or investigational drugs at any time prior the Baseline

EXCL02 · Study eye: participant received any approved

treatment for nAMD (other than vitamins and dietary supplements) at any time prior the Baseline

EXCL03 · Study eye: presence of other causes of CNV than

nAMD

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PD identifier · Protocol deviation term for reporting

EXCL05 · Study eye: CRC confirmed central subfield

affected by fibrosis, atrophy or scarring > 50% of total lesion area

EXCL06 · Study eye: CRC confirmed sub-retinal

hemorrhage ≥50% of total lesion area; or involving the fovea 1 or more disc area in size

EXCL07 · Study eye: retinal pigment epithelium rip/ tear at

Screening or Baseline

EXCL08 · Study eye: current vitreous hemorrhage or history

of vitreous hemorrhage within 4 weeks prior to Baseline

EXCL09 · Study eye: history or evidence of a concurrent

intraocular condition, trauma or medical and/ or surgery intervention prior the Baseline, within the period specified at the EXC 9 of the protocol

EXCL20 · Previous systemic treatment with any anti-VEGF

therapy

EXCL24 · Participation in investigational systemic drug,

biologic, or device study within 30 days or duration of 5 half-lives of the investigational product prior to Baseline

WITH03 · IVT injection administered after the participant

withdrew consent

WITH04 · Assessments performed after the participant

withdrew consent

TRT02 · Randomized by error and study drug was not

administered

TRT03 · Incorrect treatment kit administered in the study

eye in error

TRT05 · Study treatment injection not administered as per

protocol treatment schedule

TRT06 · Participant received expired investigational

product

TRT07 · Participant received lower or over-dose of study

treatment at a [information personnelle] visit

TRT08 · Participant received investigational product with

temperature excursion

COMD01 · Prohibited ocular medication and/ or procedure in

the study eye

COMD02 · Prohibited ocular medication in fellow eye OR

systemic medication

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Additional criteria

Additional medical

assessment will be performed

Additional medical

assessment will be performed

At visits: V2, or V3, or V4

At visits: V2, or V3, or V4, or V5

At visits: V2, or V3, or V4

Incorrect treatment

At visits: V2, or V4

With additional medical assessment

At visits: V2, or V4

At visits: V2, or V4

With additional medical assessment

At visits: V2, or V4

At visits: Before V5

Before V5, cases with ocular

(ophthalmic route)

administration of Bevacizumab anti-VEGF treatment in the fellow eye

OR

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PD identifier · Protocol deviation term for reporting · Additional criteria

Before V5, cases with non-ocular administration and anti-VEGF ATC Code.

OTH01 · BCVA assessment not performed at a scheduled · At visits: V2, or V5

visit

OTH04 · Subject potentially unmasked to study treatment · At visits: V2, or V3, or V4, or

V5

Before primary endpoint assessment

OTH05 · Unmasked personnel (or masked personnel · At visits: V2, or V3, or V4 or

accidentally unmasked) performed BCVA · V5

assessments for the study eye

OTH06 · BCVA assessment for the study eye not · At visits: V2 or V5

performed correctly with relevant potential to · With additional medical

confound the BCVA assessments · assessment

OTH20 · Missed Visit not related to COVID-19 · At visits : V5

Participants of Per Protocol Analysis set (PPS) will be analyzed according to the study treatment received.

PK Analysis Set

The PK Analysis Set (PKS) will be the analysis set used for analyzing free and total drug concentration in the subset of participants participating in the PK substudy. The PKS comprises

Subjects who sign PK sub study ICF and having at least 1 evaluable post-baseline drug concentration assessment are considered for PK substudy. However, Subjects requiring (i.e.

receiving) both eyes treatment at baseline (i.e. Day 1 as per assessment schedule) are not eligible for PK substudy. Participants receiving both the treatments (i.e. SOK583 and Eylea EU) into the study eye will be excluded from PKS. Participants will be analyzed according to the study treatment received.

Immunogenicity Analysis Set

The Immunogenicity Analysis Set (IAS) consists of all randomized patients who received at least 1 dose of the investigational treatment (SOK583 or Eylea EU) and have immunogenicity blood samples collected and analyzed at Baseline and at least 1 time point post-baseline.

Participants with positive immunogenicity at Baseline will be excluded from the IAS.

Participants receiving both the treatments (i.e. SOK583 and Eylea EU) into the study eye will be excluded from IAS. Participants will be analyzed according to the study treatment received.

VEGF Analysis Set

The VEGF Analysis Set will be the analysis set used for evaluating systemic VEGF concentrations in a subset of participants. The VEGF Analysis Set comprises those participants who received study treatment at Week 48 and have a VEGF concentration assessment at Week 52. Participants requiring (i.e. receiving) both eyes treatment during the study will be excluded. Participants receiving (by mistake) both the treatments (i.e. SOK583 and Eylea EU)

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into the study eye will be excluded from VEGF analysis set. Participants will be analyzed according to the study treatment received.

2.2.1 · Subgroup of interest

The subgroups of interest are:

• Region (US, Europe, Rest of the World)
• Age category (< 75 years and ≥ 75 years)
• Sex (male and female)
• Race (White, Other)
• Baseline BCVA category (< 64 and ≥ 64 letters)
• Baseline lesion type (predominantly classic, minimally classic, occult)
• Baseline CNV lesion size (< 0.5 mm 2 , 0.5-1.8 mm 2 , > 1.8 mm 2 ) (Latest value Collected at Screening Visit)
• Baseline intraretinal fluid status (Absent, Present)
• Baseline subretinal fluid status (Absent, Present) Subgroup analyses will be performed for the primary endpoint change from Baseline in BCVA at Week 8. The analyses of the Subgroup of interest will be descriptively only. CNV lesion size value collected before treatment administration will be analyzed as Baseline CNV lesion size values.

The subpopulation of Japanese subjects will be additionally analyzed in a specific subgroup analysis. Japanese subjects who are included in the subgroup analyses will be identified as Japanese according to the corresponding ethnicity data, irrespective of residency. The table produced for the Japanese subpopulation will be specified in the TFL Shells document. The subgroup analysis will follow the same statistical methods as described for the entire population.

Subgroup analyses will be also performed for TEAE overview and for ocular TEAEs in the study eye and for non-ocular TEAEs for the following subgroups:

• Age category (<75 years and ≥ 75 years)
• Sex (male and female)
• Region (US, Europe, Rest of the World).

2.3 · Subject disposition, demographics and other baseline

characteristics

2.3.1 · Subject disposition

The number of participants screened, and the number of participants screen failed will be presented. In addition, the number of participants re-screened will be given.

Participants disposition will be summarized (n and percentages) by the treatment group.

Percentages will be based on the number of patients in RAS.

The summary will include the following information:

• Number of participants who completed the treatment

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• Number of participants who discontinued the treatment early
• Number of participants who terminated the study prematurely, overall and by visit
• Reason for discontinuation of the treatment
• Reason for discontinuation of the study

If there were dosing errors where participants received treatment other than the one they were randomized to, separate summaries will be presented based on ‘as treated’, while the ‘as treated’ status will be derived from the majority of treatments received. If there is a tie, the latest treatment will be used.

A listing of participants who discontinued treatment earlier or prematurely discontinued study and the primary reason for discontinuation will be presented. The listing will identify the visits completed and when the study or treatment was discontinued. Additional listing for participants with differences in the disposition status for the treatment and the study, including participants with missing disposition status on the Disposition eCRF, will be presented. In addition, a listing of patients along with the PPS, IAS, VEGF and PKS analysis set that they were excluded from and the corresponding reasons will be presented.

The number of participants included in the analysis sets by treatment group will be presented.

All Enrolled set will be presented without treatment group only for Total counts. Percentages will be based on the number of participants in RAS.

All important protocol deviations will be reviewed on an ongoing basis, at a minimum once a month from First Participant First Visit (FPFV), as defined in Data Quality Plan (DQP).

The protocol deviations leading to exclusion from PPS are shown in Table 2-1. This classification concerns the impact that the important protocol deviations are expected to have on the statistical analysis of the primary endpoint. The protocol deviations leading to exclusion of participants from PPS will be summarized.

The number and percentage of participants in the FAS with important protocol deviations will be summarized by treatment group. A listing of important protocol deviations will be generated based on All Enrolled Set.

2.3.2 · Demographics and other baseline characteristics

Demographic and other baseline data including disease characteristics will be listed for All

Enrolled Set and summarized descriptively by treatment group for the FAS, PPS, SAF, and PKS. Demographic summaries will include age at screening (both as a continuous variable and using categories < 75 years and ≥ 75 years), sex, race, ethnicity, and ancestry. Baseline characteristics summary will consist of primary diagnosis of nAMD, time since diagnosis of nAMD (in days), whether nAMD is unilateral or bilateral, iris color, definition of the study eye, intraocular pressure, BCVA (both as a continuous variable and using categories < 64 letters and ≥ 64 letters), lesion type (predominately classic, minimally classic, occult), foveal involvement

(subfoveal, extrafoveal, undeterminable), CNV lesion size (tertiles), presence of subretinal fluid, presence of intraretinal fluid/cyst, and CSFT).

Relevant ocular medical histories and ocular current medical conditions at baseline for the study eye and for the fellow eye will be summarized by SOC and PT, for all participants in the FAS

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by treatment group. In addition, a similar summary will be included for the non-ocular medical histories and current medical conditions. Medical History of Disease will be listed for All

Enrolled Set

2.4 · Treatments (study treatment, concomitant therapies,

compliance)

2.4.1 · Study treatment / compliance

Study medication administration information will be listed by treatment.

The extent of exposure / compliance by treatment will be presented based on the overall number of injections and the number of participants injected per visit using the SAF.

The number and percent of participants who received study treatment, missed a treatment and missed visits or discontinued treatment will be summarized cumulatively by visit. Frequency of all observed dosing patterns up to and including Week 48, missed treatments and wrong treatments will be presented using SAF and PPS.

2.4.2 · Prior, concomitant and post therapies

Ocular and non-ocular prior medications (any medication taken up to 90 days prior to Screening) and concomitant medications (ocular and non-ocular) will be listed separately and summarized according to the ATC classification system, by treatment group using SAF. Prior medications are defined as treatments taken and stopped prior first IVT injection. Concomitant medications are defined as treatment taken at least once on or after first IVT injections (including those which were started prior first IVT injection and continued into the treatment period). Ocular medications will be presented separately for the study eye and the fellow eye. Additionally, the number and percentage of patients who had prior and concomitant non-drug therapies/ procedures performed during the study will be summarized by SOC and PT according to MedDRA terminology using SAF. Prior and concomitant non-drug therapies/procedures are defined in the same way as done for prior and concomitant medications. These summaries will be presented separately for the study eye and the fellow eye.

Prohibited concomitant medications and anti-VEGF treatments for the fellow eye will be summarized by ATC and PT according to WHODD terminology using SAF. Appendix 5.4 lists

ATC for some prohibited medications. Subjects with prohibited concomitant medications will be listed using SAF.

Prohibited Concomitant Procedures / non-drug therapies (if any) for study eye will be summarized by SOC & PT for subjects with indication of AMD. Appendix 5.4 lists for some preferred terms of prohibited procedures.

2.5 · Analysis supporting primary objective(s)

Data analysis will be performed at 2 time points. The primary analysis is to demonstrate comparability of SOK583 to Eylea EU treatment with respect to the primary endpoint. This primary analysis will be performed when all randomized participants have completed Week 40 or discontinued before Week 40. At this point, a partial database lock of the available data will be completed. The primary analysis will also include all available efficacy and safety data that

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have been collected up until the partial database lock. The final analysis will occur when all randomized participants have completed the study. A full CSR will be generated at both analysis time points.

2.5.1 · Primary endpoint(s)

Primary endpoint is the change from baseline in BCVA score at Week 8. BCVA will be assessed using the ETDRS testing charts at an initial distance of 4 meters. The change from Baseline in BCVA in letters is defined as difference between BCVA score between Week 8 and Baseline.

2.5.2 · Statistical hypothesis, model, and method of analysis

The primary aim of the study is to demonstrate equivalence of change from Baseline in BCVA score at Week 8 between patients with nAMD treated with SOK583 or with Eylea EU, without important protocol deviations which affects the primary endpoint and adherent to the treatment and completed the treatment to Week 8.

The following statistical hypotheses will be tested to assess equivalence between SOK583 and Eylea EU:

H 0 : |µ SOK583 – µ Eylea | ≥ Δ versus H 1 : |µ SOK583 – µ Eylea | < Δ, where µ SOK583 and µ Eylea are the change from baseline in BCVA score at Week 8 for SOK583 and Eylea EU, respectively.

Therapeutic equivalence in terms of change from Baseline in BCVA for EMA and PMDA requirement will be concluded if the 95% CI for the difference in mean changes is contained within the interval [−3.5, +3.5]. This is statistically equivalent to calculating 2 independent one-sided tests at 2.5%-alpha level (one in each direction), of which both have to be successful.

Therapeutic equivalence in terms of change from baseline in BCVA for FDA requirement will be concluded if the 90% CI for the difference in mean changes is contained within the interval

[−3.0, +3.0]. This is statistically equivalent to calculating 2 independent one-sided tests at a 5%- alpha level, of which both have to be successful.

ANCOVA will be performed, and the model will include treatment as a factor, and Baseline

BCVA and age as continuous covariates. The least-squares means for the treatments will be calculated and the CIs for the difference in the 2 products will be obtained from the ANCOVA model. Consistent with the two one-sided tests for bioequivalence at the 2.5% significance level

(Schuirmann 1987), 95% CIs for change from Baseline in BCVA will be derived. Similarly, 90% CIs for change from Baseline in BCVA will be derived.

Participation in the PK substudy is included as an administrative stratification factor in order to ensure the required number of participants and to limit the operational burden. Region is also included as an administrative stratification factor in order to ensure a balanced allocation of participants in each region for relevant region-specific subgroup analyses. Therefore, these

2 stratification factors will not be included in the statistical model.

The primary analysis will be performed on the PPS, which is defined in Section 2.2.

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2.5.3 · Handling of intercurrent events

Since the primary analysis is only on those participants who adhere to and complete treatment up to Week 8 and do not have important protocol deviations that would affect the primary endpoint during this time, there will be no intercurrent events for the observed PP estimand.

2.5.4 · Handling of missing values not related with intercurrent events

As primary analysis will be performed on PPS as defined in Section 2.2, there will be no missing data for primary endpoint, the change from baseline at Week 8 in BCVA scores. Therefore, no imputation for missing data will be performed for primary analysis.

2.5.5 · Sensitivity analyses

A sensitivity analysis to compare the results from the ANCOVA model for the primary estimand with a MMRM model will be performed. The MMRM model will include treatment, visit and interaction between time and treatment as categorical variables, and age and baseline BCVA as continuous variables. As the model can handle partial data from a participant when estimating the variance-covariance matrix, participants with both baseline BCVA value and at least one available value at Week 4 or Week 8 will be included in the analysis. The sensitivity MMRM analyses will be conducted using the PPS observed data.

2.5.6 · Supplementary analyses

To explore the robustness of inferences from the primary observed PP estimand, a supplementary analysis on FAS using the same statistical model of ANCOVA as for the primary analysis will be performed. Missing data will be imputed using LOCF imputation. Observed values from both scheduled and unscheduled visits will be used for the LOCF imputation. For participants with no post-baseline value, no imputation will be performed.

A sensitivity analysis to compare the results from the ANCOVA model for supplementary analysis with a MMRM model will be performed. The MMRM model will include treatment, visit and interaction between time and treatment as categorical variables, and age and baseline

BCVA as continuous variables. As the model can handle partial data from a participant when estimating the variance-covariance matrix, participants with both baseline BCVA value and at least one available value at Week 4 or Week 8 will be included in the analysis. This sensitivity

MMRM analysis will be conducted using the FAS observed data.

2.6 · Analysis supporting secondary efficacy objective(s)

The secondary efficacy objectives are:

• To evaluate if the anatomical outcome of SOK583 is similar to Eylea EU
• To evaluate if the efficacy of SOK583 is similar to Eylea EU in terms of BCVA 2.6.1 · Secondary endpoints The secondary efficacy endpoints are:
• Mean change in CSFT using SD-OCT from Baseline to Weeks 1, 4, 8, 24 and 52
• Mean change of CNV lesion size using FA from Screening to Weeks 8 and 52

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• Mean change from Baseline in BCVA score using EDTRS testing charts at Weeks 24 and 52 2.6.2 · Statistical hypothesis, model, and method of analysis No hypothesis will be tested for the secondary efficacy endpoints.

CSFT values and associated changes from Baseline will be summarized descriptively by treatment group for Baseline, Week 1, Week 4, Week 8, Week 24 and Week 52. Mean change from Baseline in CSFT to Week 52 will be graphically presented.

CNV lesion size values and associated changes from Baseline assessment will be summarized descriptively by treatment group for Baseline, Week 8 and Week 52. Mean change from Baseline in CNV lesion size to Week 52 will be graphically presented. Note that the Baseline assessment for CNV lesion size was performed at Screening. The latest CNV lesion size value collected before administration at screening visit will therefore be considered as Baseline values to derive change values for post-baseline visit.

For CNV lesion size it was assumed that if Type of CNV is “CNV ABSENT” then this would indicate that lesion shrinks to zero mm 2 . Hence, for subjectsfor whom Type of CNV is “CNV

ABSENT” and parameters “Area of Lesion within CNV status” and “Area of CNV within

Lesion” are missing or Not Applicable at a visit, lesion size values (i.e. Area of CNV within

Lesion Measurement) will be imputed to Zero values for this visit for analysis purpose only.

BCVA values and associated changes from Baseline will be summarized descriptively by treatment group for all scheduled post-baseline visits, including Week 24 and Week 52. Mean change from Baseline in BCVA to Week 52 will be graphically presented. The analyses will be done using the FAS and the PPS.

2.7 · Safety analyses

All listings and tables will be presented by treatment group.

Safety summaries (tables, figures) include only data from the on-treatment period with the exception of baseline data which will also be summarized where appropriate (e.g. change from Baseline summaries). Summary tables for AEs will summarize only on-treatment events, with a start date during the on-treatment period (TEAEs).

The on-treatment period lasts from the date of first administration of study treatment to 4 weeks after the date of the last actual administration of any study treatment.

There are no formal safety hypotheses in this study. All safety analyses will be performed using the SAF. The safety endpoints are based on the variables from the safety assessments, which include:

• Ocular and non-ocular TEAEs and SAEs
• Ophthalmic examinations
• Vital signs
• Laboratory results
• Post-injection assessments

[nom]. · C o nfi d e nti al · P a g e 2 4 of 3 8

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• A D A ( [nom] utr ali zi n g A D A u p t o W e e k 5 2) T h e r e p orti n g of c or e s af et y t o pi cs will b e d efi n e d wit h e C R S usi n g t h e s af et y pr ofili n g pl a n fl a g. T h e e C R S s af et y t o pi cs will b e fi n ali z e d b ef or e t h e ti m e of a n al ysis i m pl e m e nt ati o n (i. e. b ef or e st u d y d at a b as e l o c k) a n d d o c u m e nt e d a p pr o pri at el y.
• 7. 1 · A d v er s e e v e nt s

A T E A E is d efi n e d as a n y A E t h at d e v el o ps aft er i niti ati o n of t h e st u d y tr e at m e nts or a n y e v e nt alr e a d y pr es e nt t h at w ors e ns f oll o wi n g e x p os ur e t o t h e st u d y tr e at m e nt u ntil t h e e n d of st u d y .

All i nf or m ati o n o bt ai n e d o n A Es will b e dis pl a y e d b y tr e at m e nt gr o u p a n d p arti ci p a nt .

Tr e at e d s u bj e ct wit h c o m pl et el y missi n g st art d at e a n d e n d d at e i nf or m ati o n will b e c o nsi d er e d as T E A E. S u bj e cts wit h c o m pl et el y missi n g e n d d at e i nf or m ati o n o n A d v ers e e v e nts will b e c o nsi d er e d as O n g oi n g.

T E A E s will b e s u m m ari z e d b y pri m ar y S O C a n d P T a c c or di n g t o t h e M e d D R A t er mi n ol o g y.

N o n -tr e at m e nt-e m er g e nt A Es will b e list e d b y All E nr oll e d S et.

A n o v er vi e w t a bl e will s u m m ari z e t h e n u m b er a n d p er c e nt a g e of p arti ci p a nts wit h at l e ast 1 of t h e f oll o wi n g T E A Es: a n y T E A E, T E A E s us p e ct e d t o b e tr e at m e nt-r el at e d, s e v er e T E A E s us p e ct e d t o b e tr e at m e nt-r el at e d, S A E, S A E s us p e ct e d t o b e tr e at m e nt-r el at e d, T E A E l e a di n g t o st u d y tr e at m e nt dis c o nti n u ati o n, o c ul ar T E A E r el at e d t o st u d y pr o c e d ur e f or st u d y e y e , o c ul ar

T E A E r el at e d t o eit h er of tr e at m e nt or st u d y pr o c e d ur e or b ot h a n d T E A E l e a di n g t o d e at h (it s h o ul d b e n ot e d t h at t h e r el ati o ns hi p t o t h e o c ul ar i nj e cti o n pr o c e d ur e w as c a pt ur e d as r el ati o ns hi p t o st u d y pr o c e d ur e i n t h e e C R F). P arti ci p a nt s wit h m or e t h a n 1 T E A E i n a p arti c ul ar c at e g or y will b e c o u nt e d o nl y o n c e i n t h at c at e g or y.

T h e n u m b er ( a n d p er c e nt a g e) of p arti ci p a nts wit h T E A E will b e s u m m ari z e d i n t h e f oll o wi n g w a ys:

• b y tr e at m e nt, pri m ar y S O C a n d P T
• b y tr e at m e nt, pri m ar y S O C , P T a n d m a xi m u m s e v erit y S e p ar at e pr es e nt ati o ns will b e pr o vi d e d r el at e d t o o c ul ar e v e nts i n t h e st u d y e y e a n d f ell o w e y e a n d t o s yst e mi c e v e nts. S e nsiti vit y s af et y a n al ys es will b e p erf or m e d b y e x cl u di n g p arti ci p a nts t h os e w h o ar e r e c ei vi n g o c ul ar a nti -V E G F tr e at m e nt i n f ell o w e y e d uri n g st u d y. S e p ar at e s u m m ari es will b e pr o vi d e d f or T E A Es s us p e ct e d t o b e r el at e d t o st u d y tr e at m e nt, d e at hs, S A Es , ot h er si g nifi c a nt T E A Es l e a di n g t o st u d y dis c o nti n u ati o n. S u m m ari es will b e pr o vi d e d f or o c ul ar T E A Es i n t h e st u d y e y e r el at e d t o st u d y pr o c e d ur e b y tr e at m e nt, pri m ar y S O C a n d P T; a n d b y tr e at m e nt, pri m ar y S O C, P T a n d m a xi m u m s e v erit y.

C CI

A p arti ci p a nt wit h m ulti pl e A Es wit hi n a pri m ar y S O C is o nl y c o u nt e d o n c e t o w ar ds t h e t ot al of t h e pri m ar y S O C .

Listi n gs of d e at h s, S A Es, T E A Es l e a di n g t o st u d y tr e at m e nt dis c o nti n u ati o n, T E A E l e a di n g t o st u d y dis c o nti n u ati o n a n d st u d y tr e at m e nt r el at e d T E A Es will b e pr o vi d e d.

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2.7.1.1 Adverse events according to the risks listed in the Eylea EU Risk

Management Plan

Separate presentations of AE according to the risks listed in the Eylea EU RMP will be provided related to ocular events in the study eye and fellow eye and to systemic events. In addition, a summary of AE suspected t